36 results about "Degarelix" patented technology

The invention provides methods and dosing regimens for safely and effectively treating androgen-dependent prostate cancer with a gonadotrophin releasing hormone (GnRH) antagonist without causing a testosterone spike and / or other side effect of GnRH agonist therapy such as a urinary tract infection, or an arthralgia-related or cardiovascular side effect. The present disclosure also provides for methods for treating prostate cancer in a patient with a history of at least one cardiovascular event, wherein administration of degarelix to the subject decreases the likelihood of developing or experiencing an additional cardiovascular event compared to treatment with a gonadotrophin releasing hormone (GnRH) agonist.

In a step-wise synthesis of degarelix comprising 0.3% by weight or less of 4-([2-(5-hydantoyl)]acetylamino)-phenylalanine analog on (solid support)-NH2 a step comprises providing a solution of an amino acid or peptide of which the α-amino group is protected by Fmoc; contacting the support with the solution in the presence of reagent for forming a peptide bond between a carboxyl group of the amino acid or peptide and (solid support)-NH2; removing Fmoc by contacting the support with an organic base, in particular piperidine, in an organic solvent. Also disclosed is degarelix of high purity prepared by the method of the invention and the use of Fmoc in the synthesis of degarelix.

The present invention relates to a liquid (or solution)-phase manufacturing process for preparing the decapeptide Degarelix, its protected precursor, and other useful intermediates. The invention further relates to polypeptides useful in the solution-phase manufacturing process and to the purification of Degarelix itself. Degarelix can be obtained by subjecting a Degarelix precursor according to formula (II): (P1)AA1-AA2-AA3-AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2 (II) or a salt or solvate thereof, to a treatment with a cleaving agent in an organic solvent, wherein P1 is an amino protecting groups; preferably acetyl; P4 is hydrogen or a hydroxy! protecting group, preferably a hydroxyl protecting group; P6 is hydrogen or an amino protecting groups; preferably an amino protecting groups; and P8 is an amino protecting group.

The invention discloses a solid-phase synthesis method of degarelix. The solid-phase synthesis method of degarelix comprises the following steps: on the basis of taking Fmoc-amino resin as a solid-phase carrier, replacing orotic acid fragments connected with an alanine benzene ring in the fifth site and an amino in the fourth site with ivdde, and performing sequential condensation reaction from the end C to the end N so as to connect 10 protected amino acids, thereby obtaining a full-protective peptide resin; then removing the Fmoc protecting group of end N D-Nal, acetylating by using acetic anhydride and pyridine, replacing ivDde with Hor, cutting the peptide resin by using a splitting agent, and precipitating by using frozen diethyl ether to obtain crude peptide. Besides, the invention also relates to a method for synthesizing a raw material Fmoc-Aph(ivDde)-OH by use of ivDde-OH and Fmoc-Aph-OH. The solid-phase synthesis method of degarelix has the advantages that the ivDde is introduced to synthesize decapeptide firstly and then the Hor is used as a substitute to avoid a rearrangement side reaction; the solid-phase synthesis method is simple in process steps, easy to control, low in influence on a human body and the environment, high in yield, and suitable for large-scale production.

The present invention relates to a liquid (or solution)-phase manufacturing process for preparing the decapeptide Degarelix, its protected precursor, and other useful intermediates. The invention further relates to polypeptides useful in the solution-phase manufacturing process and to the purification of Degarelix itself. Degarelix can be obtained by subjecting a Degarelix precursor according to formula II: (P1)AA1-AA2-AA3-AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2 (II) or a salt or solvate thereof, to a treatment with a cleaving agent in an organic solvent, wherein P1 is an amino protecting groups; preferably acetyl; P4 is hydrogen or a hydroxyl protecting group, preferably a hydroxyl protecting group; P6 is hydrogen or an amino protecting groups; preferably an amino protecting groups; and P8 is an amino protecting group.

The invention discloses synthesis of degarelix by a solid phase segment method, wherein Fmoc-amino acid is connected with resin so that Fmoc-amino acid-resin can be obtained; a solid phase synthesis method is adopted, and the steps of orderly connecting amino acid from the end C to the end N and removing the Fmoc group are carried out, so that Fmoc protected polypeptide resin can be obtained; the method comprises the following steps of: (1) forming polypeptide resin as shown in formula III and polypeptide resin as shown in formula IV, respectively; (2) mixing the polypeptide resin as shown in formula III with 1-5% of trifluoroacetic acid (TFA), connecting L-4,5-dihydroorotate to the side chain amino of the polypeptide resin after the protecting group of the sixth amino acid residue at the end C is removed, and then removing the Fmoc group to obtain polypeptide resin as shown in formula V; removing the Fmoc group of the polypeptide resin as shown in formula IV and acetylating the polypeptide resin, thereby obtaining polypeptide resin as shown in formula VI, and then cutting to obtain segments as shown in formula VII; (3) coupling the polypeptide resin as shown in the formula V with the segments as shown in the formula VII, thereby obtaining the polypeptide resin as shown in formula II; (4) separating polypeptide on the polypeptide resin as shown in the formula II from the resin, thereby obtaining degarelix as shown in formula I.

The invention relates to the field of synthesis of medicines and discloses a method for synthesizing degarelix. The method for synthesizing the degarelix comprises the following steps: enabling D-alanine with a protective group coupled with an N end to carry out esterification reaction with amino resin with a protective group coupled with an amino in the presence of a condensation reagent and an activation reagent to obtain peptide resin 1; extending and coupling other protective amino acids one by one by starting from the peptide resin 1 according to a sequence from C end to N end of the amino acid sequence of the degarelix in the presence of the condensation reagent and the activation reagent, to obtain corresponding peptide resins after extending and coupling each time and finally obtain degarelix resin, then carrying out acidolysis to obtain a degarelix crude product, and purifying the degarelix crude product to obtain a degarelix pure product. By virtue of the method for synthesizing the degarelix, a proper synthesizing scheme is selected; the adaptive amino resin and an acidolysis solution are selected; the overall synthesis process is optimized; the purity of the degarelix is obviously improved; the degarelix has a relatively high total yield and is free of pollution to any environment.

The present invention relates to the field of polypeptide synthesis, in particular to a method for preparing degarelix using a solid-liquid combination chemical method. The present invention synthesizes a fragment peptide Ac-D-2Nal-D-4Cpa-D-3Pal-Ser(tBu) for the first time ‑4Aph(Fmoc)‑OH is used for the solid-phase synthesis of degarelix, the synthesis process is simple, the raw materials used are cheap and easy to obtain, and it is easy to scale up production; the present invention avoids the use of highly toxic reagent HF, and adopts TFA combination cracking, after purification, The refined peptide with a purity of 99.5% was obtained by lyophilization, and the total yield reached 65%.

The invention relates to a solid-phase synthetic method for degarelix. The method comprises the following steps of: 1) reacting resin with Fmoc-D-Ala-OH to obtain Fmoc-D-Ala-resin, wherein the resin is amino resin; 2) sequentially connecting according to the amino acid sequence of the degarelix by adopting an Fmoc solid-phase synthetic strategy; 3) removing Fmoc from a N terminal, and acetylating by using acetic anhydride and pyridine; 4) removing a protective group X on the 6th amino acid residue -4Aph(X) from a C terminal; 5) connecting L-4,5-dihydrooroticacid to a side-chain amino group of the 6th amino acid residue -4Aph at the C terminal; 6) cutting peptide resin by using a cracking reagent, precipitating by using anhydrous ether, and centrifuging to obtain crude peptide; and 7) purifying and separating to obtain the degarelix. The method is easy to operate and slightly damages human bodies and environments; and by the process, the content of impurities is effectively reduced, and the large-scale production can be performed.

The use of degarelix in the treatment of endometriosis, in particular in the treatment of endometriotic ovarian cysts and recurrent endometriotic lesions following surgery and in the treatment of endometriosis and / or endometriotic ovarian cysts in patients who plan to undergo assisted reproduction, is described, wherein this treatment is performed before the patients are subjected to assisted reproduction; degarelix is administered for this purpose as a single dose of 80-120 mg, preferably 80 mg, subcutaneously.